DESCRIPTION (Applicant's abstract): As an early event in CO2 sensing, changes in membrane excitability have been demonstrated in brainstem CO2 chemo sensitive neurons, which seem to result from alternations in synaptic transmission, transporter activity and/or ion channel activation. Indeed, studies including ours have shown that K+ channels are the key players in controlling membrane excitability in these chemo sensitive neurons. We have found that the hypercapnia-induced depolarization is attenuated by antagonism of K+ channels, while blockade of synaptic transmission and several other ion channels has no effect. We have thereafter studied these CO2-sensitive K+ channels and demonstrated a novel CO2 sensing mechanism in these channels. This mechanism relies on the inherent pH-sensing and channel-gating processes of inward rectifier K+ channels, allowing the change in PCO2 levels to be coupled to a nonexpanding change in membrane excitability. Among these CO2-sensitive K+ channels, the heteromeric Kir4.1-Kir5.1 is particularly interesting. With a linear working range at physiologic pH levels, these channels can detect both hypercapnia and hypocapnia. These plus their brainstem-specific expression make them the highly promising candidates for the potential CO2 sensing molecules in the central CO2 chemoreceptors. Clearly, detailed studies of the molecular mechanisms underlying the CO2 sensing in these K+ channels may yield important information of CO2 chemoreception. Thus, we have proposed experiments to test three specific hypotheses: 1) the heteromeric Kir4.1 -Kir5.1 channels act as CO2 sensors 2) the Kir4.1 -Kir5.1 channels are specifically expressed in brainstem neurons; and 3) CO2 enhances membrane excitability of chemo sensitive neurons by inhibiting the Kir4.1 -Kir5.1 channels. The outcome of these studies will not only improve our understanding of CO2 chemo receptive physiology but also may help the design of medical interventions by manipulating these cellular inherent CO2-sensing and responding mechanisms in the treatment and prevention of certain illnesses that are related to the CO2 sensation and modulation in central and peripheral cells.